RS62845B1 - Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery - Google Patents

Description

Description

AREA

[0001] This disclosure relates to ophthalmic compositions containing solid complexes of an active pharmaceutical ingredient and cyclodextrin, to methods of their preparation and their use. The present disclosure also relates to the bottom-up preparation of novel aqueous eye drop compositions containing drug/cyclodextrin nanoparticles.

BACKGROUND

[0002] In this specification, where a document, act or object of knowledge is mentioned or discussed, that reference or discussion does not constitute an acknowledgment that this document, act or object of knowledge or any combination thereof were publicly available on the priority date, known to the public, were part of general knowledge, or that they in any way formed part of the state of the art in accordance with the applicable constitutional provisions; or known to be relevant to attempting to solve any problem addressed by this specification.

[0003] According to the National Eye Institute, a division of the National Institutes of Health, eye conditions cause an estimated economic burden of $139 billion in America alone. This number is not surprising considering that age-related macular degeneration (AMD) is diagnosed in 2.1 million Americans, glaucoma is diagnosed in 2.7 million Americans, diabetic retinopathy is diagnosed in 7.7 million Americans, and cataracts are diagnosed in 24 million Americans. Eye conditions are not just a problem in the United States. In fact, it is estimated that approximately 285 million people worldwide are visually impaired.

[0004] Most eye conditions can be treated and/or controlled to reduce negative effects, including total blindness. In order to overcome this significant problem, the World Health Organization (WHO) has approved a plan of action with the goal of reducing 25% of avoidable visual impairment worldwide by 2019. In its efforts, the WHO plans to reduce the effects of eye conditions such as diabetic retinopathy, glaucoma, and retinitis pigmentosa, which represent the majority of cases of irreversible blindness worldwide. However, current therapies for eye conditions are limited by difficulties in delivering effective doses of drugs to targeted tissues in the eye.

[0005] In current therapies, topical application of eye drops is the preferred means of drug delivery to the eye due to the convenience and safety of eye drops compared to other routes of ophthalmic drug administration such as intravitreal injections and implants (Le Bourlais, C., Acar, L., Zia, H., Sado, P.A., Needham, T., Leverge, R., 1998. Ophthalmic drug delivery systems—Recent advances. Progress in Retinal and Eye Research 17, 33-58). Drugs are mainly transferred by passive diffusion from the surface of the eye to the eye and surrounding tissues where, according to Fick's law, the drug is drawn into the eye by the gradient of dissolved drug molecules. Passive diffusion of drugs into the eye is hindered by three main obstacles (Gan, L., Wang, J., Jiang, M., Bartlett, H., Ouyang, D., Eperjesi, F., Liu, J., Gan, Y., 2013. Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug Discov. Today 18, 290-297; Loftsson, T., Sigurdsson, H.H., Konradsdottir, S., Stefansson, E., 2008. Topical drug delivery to the posterior segment. Pharmazie 63, 171-179. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv.

[0006] The first major obstacle is the solubility of the aqueous drug. In previously known ophthalmic compositions, only dissolved drug molecules can penetrate through biological membranes into the eye. Consequently, ophthalmic drugs must have sufficient solubility in the aqueous tear fluid to penetrate the eye. Jansook et al., "yCD/HPyCD mixtures as solubilizer: solid-state characterization and sample dexamethasone eye drop suspension", Journal of pharmacy and pharmaceutical sciences, vol.13, no.3, pages 336-350, discloses the preparation of the dexamethasone/γ-cyclodextrin complex by autoclaving a composition that includes both components.

[0007] Another main obstacle is the high speed of circulation of tear fluid and thus the reduction of the concentration of dissolved drug molecules. After instillation of eye drops (25-50 µl) on the precorneal surface, the greater part of the drug solution dries on the surface of the eye and the tear volume returns to the normal resident volume of about 7 µl. After that, the tear volume remains constant, but the concentration of the drug decreases due to dilution by circulation and absorption of the drug in and out of the cornea.

The value of the first-order rate constant for the drainage of eye drops from the surface is usually about 1.5 min<-1> in humans after the initial rapid drainage. Normal tear turnover is about 1.2 µl/min in humans, and the precorneal half-life of topically applied drugs is between 1 and 3 minutes (Sugrue, M.F., 1989. The pharmacology of antiglaucoma drugs. Pharmacology & Therapeutics 43, 91-138).

[0008] The third main obstacle is the slow penetration of the drug through the membrane barrier, ie. cornea and/or conjunctivitis. Drug molecules must separate from the aqueous exterior into the membrane before they can passively penetrate the membrane barrier. The result is that generally only a few percent of the administered drug dose is delivered to the eye tissues. The main part (50-100%) of the given dose will be absorbed from the nasal cavity into the systemic circulation of the drug, which can cause various side effects.

[0009] This disclosure seeks to assist the WHO plan to reduce avoidable visual impairment by providing an ophthalmic composition and method of making an ophthalmic composition that overcomes the barriers of passive drug diffusion in the eye. In these efforts, applicants provide a process for the preparation of an ophthalmic composition that overcomes the major obstacles to passive drug diffusion by (1) increasing the solubility of poorly soluble drugs, (2) increasing the pre-corneal half-life of topically applied drugs, and (3) sequestering drug molecules from the aqueous exterior into the membrane to allow passive saturation of the membrane barrier. In exemplary embodiments, ophthalmic compositions comprising a combination of such features are provided.

SUMMARY

[0010] The invention is defined in the patent claims. Cyclodextrins are well known for enhancing the solubility and bioavailability of hydrophobic compounds. In aqueous solutions, cyclodextrins form inclusion complexes with many active pharmaceutical ingredients. The bottom-up preparation of the active pharmaceutical ingredient/cyclodextrin complex involves suspending the active pharmaceutical ingredient and cyclodextrin in an aqueous medium and heating the resulting suspension. After dissolving the active pharmaceutical ingredient and cyclodextrin, complexes of the active pharmaceutical ingredient and cyclodextrin are formed. The warm solution is then cooled to precipitate solid complexes of the active pharmaceutical ingredient and cyclodextrin.

[0011] Applicants have surprisingly discovered that the particle diameter and viscosity of the composition can be adjusted by heating and cooling phases in the presence of stabilizing polymers in the aqueous medium. In order to prevent or substantially inhibit or reduce the formation of impurities, such as degradation product derived from the active pharmaceutical ingredient and/or excipient, applicants have discovered that excessive heating of the substrate should be avoided and that the warm solution should be rapidly cooled to room temperature.

[0012] Furthermore, the composition according to this disclosure exhibits increased viscosity that prevents sedimentation of microparticles during storage and also preferably increases the contact time of the particles on the surface of the eye thereby improving the bioavailability of the active pharmaceutical ingredient.

[0013] Applicants have disclosed an ophthalmic composition and method of making the composition, which overcomes the known obstacles of passive drug diffusion.

[0014] The first object of this disclosure is an ophthalmic composition that includes, in an ophthalmologically acceptable base, a solid complex that includes an active pharmaceutical ingredient and cyclodextrin, wherein that composition includes less than 2%, more specifically less than 1%, even more specifically less than 0.8 wt.% of impurities in relation to the mass of the active pharmaceutical ingredient.

[0015] Another object of this disclosure is an ophthalmic composition comprising, in an ophthalmologically acceptable base, a solid complex comprising an active pharmaceutical ingredient and a cyclodextrin; and polymer; wherein the viscosity of the composition is from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0016] The third object of this disclosure is an ophthalmic composition that includes, in an ophthalmologically acceptable base, a solid complex that includes dexamethasone and γ-cyclodextrin, wherein that composition includes less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2 wt.% of 16,17-unsaturated dexamethasone or enol aldehyde mixture in relation to the mass of dexamethasone.

[0017] A fourth subject of this disclosure is an ophthalmic composition comprising, in an ophthalmically acceptable carrier, a solid complex comprising dexamethasone and γ-cyclodextrin; and polymer; wherein the viscosity of the composition is from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0018] The ophthalmic compositions of the present disclosure are generally in the form of microsuspensions comprising a solid complex that can exhibit a diameter of less than about 100 µm. Compositions comprising natural α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin and the methods provided by the present disclosure provide from about 10-fold to about 100-fold increase in the concentration of available dissolved active pharmaceutical ingredient over conventional ophthalmic compositions prepared by well-known methods. Furthermore, the exemplary methods provide an ophthalmic composition of reduced impurity concentration and/or increased viscosity.

[0019] The present disclosure also provides methods for the preparation of ophthalmic compositions with a high concentration of active pharmaceutical ingredient/cyclodextrin complex microparticles. Furthermore, the methods of the present disclosure provide an ophthalmic composition of reduced impurity concentration and/or increased viscosity.

[0020] As such, the fifth subject of this disclosure is a method of preparing an ophthalmic composition, wherein the active pharmaceutical ingredient and cyclodextrin are suspended in an ophthalmologically acceptable medium to form a suspension. The suspension is then heated at a temperature T1 lower than 120°C for a time t until the active pharmaceutical ingredient and the cyclodextrin are substantially dissolved in the ophthalmically acceptable medium. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0021] The sixth object according to this disclosure is a method of preparing an ophthalmic composition wherein cyclodextrin is suspended in an ophthalmologically acceptable medium to form a suspension.

The suspension is then heated until the cyclodextrin is substantially dissolved in the ophthalmically acceptable medium. The active pharmaceutical ingredient is then added in solid form to said solution at a temperature T1 below 120°C and the mixture is heated at a temperature T1 below 120°C for a time t until the active pharmaceutical ingredient is substantially dissolved in the ophthalmically soluble vehicle. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0022] The seventh object according to this disclosure is a method of preparing an ophthalmic composition, wherein the active pharmaceutical ingredient is suspended in an ophthalmically acceptable carrier to form a suspension and said suspension is heated until the active pharmaceutical ingredient is essentially dissolved in the ophthalmically soluble carrier. Separately, the cyclodextrin is suspended in an ophthalmically acceptable vehicle to form a suspension and said suspension is heated until the cyclodextrin is substantially dissolved in the ophthalmically acceptable vehicle. Both compositions are then mixed at a temperature T1 below 120°C and the mixture is heated at a temperature T1 below 120°C for a time t. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0023] The eighth object according to this disclosure is a method of preparing an ophthalmic composition, wherein dexamethasone and γ-cyclodextrin are suspended in an ophthalmologically acceptable medium to form a suspension. The suspension is then heated at a temperature T1 below 120°C for a time t until the dexamethasone and γ-cyclodextrin are substantially dissolved in the ophthalmically acceptable medium. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0024] The ninth object according to this disclosure is a method of preparing an ophthalmic composition, wherein γ-cyclodextrin is suspended in an ophthalmologically acceptable medium to form a suspension. This suspension is then heated until the γ-cyclodextrin is substantially dissolved in the ophthalmically acceptable medium. Dexamethasone is then added in solid form to said solution at a temperature T1 below 120°C and the mixture is heated at a temperature T1 below 120°C for a time t until the dexamethasone is substantially dissolved in the ophthalmically acceptable medium. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0025] A tenth subject according to this disclosure is a method of preparing an ophthalmic composition, wherein dexamethasone is suspended in an ophthalmically acceptable medium to form a suspension, and said suspension is heated until the dexamethasone is substantially dissolved in the ophthalmically acceptable medium. Separately, γ-cyclodextrin is suspended in an ophthalmically acceptable vehicle to form a suspension, and said suspension is heated until the γ-cyclodextrin is substantially dissolved in the ophthalmically acceptable vehicle. Both compositions are then mixed at a temperature T1 below 120°C and the mixture is heated at a temperature T1 below 120°C for a time t. The resulting solution is then cooled to temperature T2 to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0026] The eleventh object according to the present disclosure is an ophthalmic composition obtainable by the method according to the present disclosure.

[0027] The twelfth subject according to this disclosure is an ophthalmic composition according to this disclosure or prepared according to the method of disclosure for use in the treatment of an eye condition, more specifically an anterior eye condition or a posterior eye condition, more specifically uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.

[0028] The thirteenth object according to this disclosure is an ophthalmic composition according to this disclosure or prepared according to a method according to this disclosure for use in the treatment of macular edema, wherein said composition is topically applied to the eye in an amount of 1 drop of the composition three times a day.

[0029] A fourteenth object according to this disclosure is the use of an ophthalmic composition according to this disclosure or prepared according to a method according to this disclosure in the form of an eye drop solution.

[0030] In exemplary embodiments, the ophthalmic composition comprises an active agent drug/cyclodextrin complex dissolved in an aqueous eye drop vehicle. The ophthalmic composition is generally in the form of a microsuspension comprising an active agent complex less than about 100 µm in diameter. The compositions and methods provided in the exemplary embodiments provide about a 10- to 100-fold increase in the concentration of dissolved active agent (ie, drug) available in conventional ophthalmic compositions prepared by well-known methods. Furthermore, the exemplary methods provide an ophthalmic composition with a reduced concentration of degradation products.

[0031] The term "active agent," as used herein, may also refer, for example, to a pharmaceutical ingredient, an active pharmaceutical ingredient, an ophthalmically active pharmaceutical ingredient, or a drug (or variations thereof). And, as used herein, these terms (and their variations) may be considered equivalent and interchangeable. Exemplary embodiments provide methods for preparing ophthalmic compositions with a high concentration of the microparticle/cyclodextrin active agent complex, and do not generate or produce byproducts and/or degradation products for at least 90 days when stored at room temperature.

[0032] According to one method, the active agent (or drug or other equivalent term) and at least one cyclodextrin are suspended in an aqueous eye drop vehicle to provide a milky suspension. The suspension is heated for a sufficient period of time at a sufficient temperature until the drug and cyclodextrin dissolve in the aqueous eye drop solution, or until a degradation product and/or by-product is formed or essentially formed. Once the drug and cyclodextrin dissolve, the milky suspension turns into an essentially clear solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin microparticle complex.

[0033] In another method, the active agent, at least one cyclodextrin, and at least one polymer are suspended in an aqueous eye drop vehicle to provide a milky suspension. The suspension is heated for a sufficient period of time at a sufficient temperature until the drug, cyclodextrin, and polymer are dissolved or substantially dissolved in the aqueous eye drop solution, and a degradation product and/or by-product is or is not substantially formed. When the drug, cyclodextrin, and polymer dissolve, the milky suspension turns into an essentially clear solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin/microparticle polymer complex.

[0034] In a further process, at least one cyclodextrin is suspended in the aqueous eye drop vehicle to provide a milky suspension. The suspension is heated for a sufficient period of time at a sufficient temperature until the cyclodextrin is dissolved (or substantially dissolved) in the aqueous eye drop solution, and the degradation product and/or by-product is formed or substantially not formed. When the cyclodextrin dissolves, the milky suspension turns into an essentially clear solution. The active agent is added to the heated aqueous suspension, the solution being stirred, until the drug is dissolved or substantially dissolved in the solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin microparticle complex.

[0035] Again in another process, cyclodextrin and at least one polymer are suspended in an aqueous eye drop vehicle to provide a milky suspension. The suspension is heated for a sufficient period of time at a sufficient temperature until the cyclodextrin and polymer are dissolved or substantially dissolved in the aqueous eye drop solution, and a degradation product and/or by-product is or is not substantially formed. Once the cyclodextrin and polymer are dissolved, the milky suspension turns into an essentially clear solution. The active agent is added to the heated aqueous suspension, stirring the solution while the drug dissolves in the solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin/microparticle polymer complex.

[0036] Again in another process, at least one cyclodextrin is suspended in water or an aqueous eye drop vehicle to provide a milky suspension. Separately, the drug is suspended in water or cyclodextrin-free eye drop vehicle to provide a milky suspension. The two suspensions were sterilized, for example, by heating in an autoclave at 121°C for 20 minutes. Then, the two suspensions or warm solutions are allowed to cool to about 95°C before mixing to form a substantially clear solution, and until no degradation product and/or byproduct is formed or substantially formed. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin microparticle complex.

[0037] In a non-limiting embodiment, at least one cyclodextrin is suspended in water or an aqueous eye drop vehicle to provide a milky suspension. Separately, the active pharmaceutical ingredient is suspended in water or an eye drop vehicle that does not contain cyclodextrin to provide a milky suspension. The two suspensions are heated or sterilized, for example, by heating in an autoclave at 121°C for 20 minutes. The two suspensions or hot solutions are then mixed together and the temperature is adjusted to about 90°C to about 95°C to form a substantially clear solution, and until no or substantially no degradation product and/or byproduct is formed. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin microparticle complex.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] These and other features of the present disclosure will now be described with reference to the drawings of certain embodiments which are intended to illustrate and not to limit the disclosure.

Fig.1 shows the structures of natural α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

Fig.2 shows the effect of self-aggregation of γ-cyclodextrin on the solubilization of the active pharmaceutical ingredient (dexamethasone). Phase solubility profiles of dexamethasone and natural γ-cyclodextrin (yCD) in aqueous eye drops. The shaded curve represents the solubility of the active pharmaceutical ingredient (•), the dashed curve represents the solubility of yCD (∘), and the straight line represents the theoretical amount of dissolved yCD in the aqueous eye drop medium. An excess of dexamethasone was added to a solution containing 0 to 20% (w/v) yCD in an ophthalmically acceptable medium containing benzalkonium chloride (0.02% w/v), sodium edetate (0.1% w/v), and sufficient sodium chloride to make the solution isotonic.

[0039] Therefore, the amount of drug dissolved in the solution is constant at yCD concentrations above 3% (w/v). The amount of yCD dissolved in the solution increases more slowly than the amount of yCD added to the media, with the change becoming linear only after 10% (w/v). This shows that at yCD concentrations between about 3-10% (w/v), all yCD added to the media form solid complexes with the drug and precipitates. At yCD concentrations above 10% (w/v), the amount of dissolved yCD shows a linear increase again.

DETAILED DESCRIPTION

[0040] The patents, published applications, and scientific literature referenced herein establish the knowledge of the skilled person. Any conflict between any reference made herein and the specific teachings of this specification shall be resolved in favor of the latter. Similarly, any conflict between the art-accepted definition of a word or phrase and the definition of a word or phrase as specifically set forth in this specification shall be resolved in favor of the latter.

[0041] As used herein, whether in the transitional phrase or in the body of the patent claim, the terms "comprising" and "comprising" should be interpreted to have an open meaning. That is, the terms should be interpreted as being synonymous with the phrases "having the least" or "including the least". When used in the context of this process, the term "comprising" means that this process includes at least the listed steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the listed features or components, but may also include additional features or components.

[0042] The terms "consisting essentially of" or "consisting essentially of" have a partially closed meaning, that is, they do not allow the inclusion of phases or components that would fundamentally change the key characteristics of the process or composition; for example, phases or features or components that will significantly interfere with the desired properties of the compounds or compositions described herein, i.e., the process or composition is limited to specific phases or materials and those that do not materially affect the basic and novel features of the process or composition.

[0043] The terms "consisting of" and "consisting of" are closed terminology and allow the inclusion of said phases or features or components.

[0044] As used herein, the singular forms "one," some" and "that" specifically also include the plural forms of the terms to which they refer, unless the context clearly dictates otherwise.

[0045] The term "about" is used herein to mean approximately, in the region of, roughly, or about. When the term "about" is used in connection with a numerical range, that range is changed by extending the limits above and below the defined numerical values. In general, the term "about" or "approximately" is used herein to vary the numerical value above and below the specified value by a deviation of 20%.

[0046] The term "dissolved" or "substantially dissolved" is used herein to refer to the solubilization of a solid in solution. A solid may be considered to be "dissolved" or "substantially dissolved" in a solution when the resulting solution is clear or substantially clear.

[0047] The term "clear" is used herein to denote a transparent or imperfectly transparent solution. Therefore, a "clear" solution has a turbidity measured according to ISO standards of ≤100 nephelometric turbidity units (NTU), preferably ≤50 NTU.

[0048] The term "substantially clear" is used herein to denote a transparent or imperfectly transparent solution. Therefore, an "essentially clear" solution has a turbidity according to ISO standards of ≤100 nephelometric turbidity units (NTU).

[0049] As used herein, the term "turbid" or "substantially turbid" or refers to a solution with a turbidity according to ISO standards greater than 100 NTU.

[0050] As used herein, the term "milky" or "substantially milky" refers to a solution with a turbidity according to ISO standards greater than 100 NTU, preferably greater than 200 NTU.

[0051] As used herein, specifying a numeric range for a variable is intended to convey that the variable may be equal to any value within that range. Therefore, for a variable that is inherently discrete, that variable can be equal to the value of any integer, including the endpoints of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any actual value of the numeric range, including the endpoints of the range. As an example, a variable described as having values between 0 and 2 may be 0, 1, or 2 for variables that are inherently discrete, and may be 0.0, 0.1, 0.01, 0.001, or any other real value for variables that are inherently continuous.

[0052] In the specification and claims, singular forms include plural counterparts unless the context dictates otherwise. As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not in the "exclusive" sense of "any of two/or."

[0053] The technical and scientific terms used here have the meaning commonly understood by a person skilled in the art and to which this description refers, unless otherwise defined. References are made herein to various methodologies and materials known to those skilled in the art. Standard reference works defining the general principles of pharmacology and pharmaceuticals include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill Companies Inc., New York (2001) and Remington, The Science and Practice of Pharmacy, 22nd Ed., Philadelphia (2013).

[0054] As used here, the term "wt.% of compound X in relation to the volume of the composition", also abbreviated as "% w/v", corresponds to the amount of compound X in grams that is introduced into 100 mL of the composition.

[0055] As used herein, the term "microparticle" refers to a particle with a diameter D50 of 1 µm or greater up to about 200 µm. The term "nanoparticle" refers to a particle with a diameter D50 of less than 1 µm.

[0056] In exemplary embodiments, the diameter, which may be D50, is 1 µm or greater up to about 200 µm; and the term "nanoparticle" refers to a particle with a D50 of less than about 1 µm.

[0057] As used herein, an "ocular condition" is a disease, minor disease, or other condition affecting or involving the eye, one of the parts or regions of the eye, or surrounding tissues such as the lacrimal glands. Broadly speaking, the eye includes the eyeball and the tissues and fluids that make up the eyeball, the periocular muscles (such as the oblique and rectus muscles), the part of the optic nerve that is inside or near the eyeball, and surrounding tissues such as the lacrimal glands and eyelids.

[0058] As used herein, an "anterior ocular condition" is a disease, minor disease, or condition affecting or involving the anterior (ie, front of the eye) ocular region or site, such as the periocular muscle nerve, eyelid, lacrimal gland, or tissue or fluid of the eyeball located in front of the posterior wall of the lens capsule or ciliary muscles.

[0059] Thus, an anterior ocular condition primarily affects or involves one or more of the following: the iris, cornea, anterior chamber, pupil, lens, or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior ocular region or site. The anterior eye condition is also considered here as an extension of the lacrimal apparatus. More specifically, the lacrimal glands that secrete tears, and their secretory ducts that transport tear fluid to the surface of the eye.

[0060] Moreover, the anterior eye condition affects or involves the posterior chamber, which is behind the retina but in front of the posterior wall of the lens capsule.

[0061] "Posterior ocular condition" is a disease, minor disease, or condition that primarily affects or involves the posterior ocular region or site such as the layer of the eye socket or sclera (in a position beyond alignment through the posterior wall of the lens capsule), the vitreous, the vitreous chamber, the retina, the optic nerve (i.e., the optic disc), and the blood vessels and nerves that vascularize or innervate the posterior ocular region or site.

[0062] Therefore, the posterior eye condition may include a disease, a minor disease, or a condition such as, for example, macular degeneration (such as non-exudative age-related macular degeneration and exudative age-related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal artery occlusive disease; central retinal vein occlusion; uveitic disease of the retina; retinal detachment; ocular trauma affecting the posterior ocular site or location; posterior eye condition caused by or affected by ocular laser treatment; posterior eye conditions caused by or affected by photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a posterior eye condition because the therapeutic goal is to prevent loss or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (ie, neuroprotection).

[0063] An anterior eye condition includes a disease, minor disease or condition such as, for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; kidney disease; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; diseases of the eyelids; diseases of the tear apparatus; obstruction of tear ducts; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma may also be considered an anterior eye condition because the clinical goal of glaucoma treatment may be to reduce aqueous humor hypertension in the anterior chamber of the eye (ie, to reduce intraocular pressure).

[0064] This description relates to and is directed to ophthalmic compositions for topical delivery of a drug to the eye(s) and to procedures for the treatment of an eye condition, such as an anterior eye condition or a posterior eye condition or an eye condition that can be characterized as both an anterior eye condition and a posterior eye condition.

Solid complex of cyclodextrin and active pharmaceutical ingredient

[0065] The composition according to the present disclosure comprises a solid complex comprising an active pharmaceutical ingredient and a cyclodextrin. A complex comprising an active pharmaceutical ingredient and a cyclodextrin may be designated as an "active pharmaceutical ingredient/cyclodextrin complex" or a "drug/cyclodextrin complex." When the active pharmaceutical ingredient is dexamethasone and the cyclodextrin is γ-cydodextrin, the complex comprising dexamethasone and γ-cyclodextrin may be designated as "dexamethasone/γ-cyclodextrin complex".

[0066] The solid complex compositions of the present disclosure may be an aggregate of the complex. The aggregate of the complex may correspond to the aggregate of a plurality of complexes, more specifically to a plurality of inclusion complexes comprising the active pharmaceutical ingredient and cyclodextrin.

[0067] According to one embodiment, the ophthalmic composition according to the present disclosure is a microsuspension. The term "microsuspension" is intended to mean a composition comprising a solid complex of microparticles suspended in a liquid phase.

[0068] More specifically, the ophthalmic composition of the present disclosure comprises a solid complex with a diameter D50 of less than about 100 µm, more specifically about 1 µm to about 100 µm. In one embodiment, the diameter D50 may be in the range of about 1 µm to about 25 µm, more specifically about 1 µm to about 20 µm, more specifically about 1 µm to about 10 µm, even more specifically about 2 µm to about 10 µm, still more specifically about 2 µm to about 5 µm or about 3 µm to about 8 µm. Diameter D50 can be measured according to the test procedure described here.

[0069] According to the European Pharmacopoeia (01/2008:1163) eye drops in the form of a suspension should correspond to the following: for every 10 µg of solid active substance, at most about 20 particles have a maximum dimension greater than about 25 µm, and at most about 2 of these particles have a maximum dimension greater than about 50 µm. None of the particles can have a maximum dimension greater than about 90 µm. The compositions according to this disclosure comply with the requirements of the European Pharmacopoeia (01/2008:1163).

[0070] In general, it is recommended that the particle sizes in the aqueous eye drop suspension be kept to a minimum, preferably below about 10 µm, to prevent eye irritation. Furthermore, the rate of sedimentation in aqueous suspensions is proportional to the particle diameter, with the sedimentation of larger particles being faster than the rate of small particles if all other factors are assumed to be constant.

Cyclodextrin

[0071] The composition of the present disclosure comprises a cyclodextrin. A composition according to the present disclosure may comprise a mixture of cyclodextrins.

[0072] Cyclodextrins, which are also known as cycloamyloses, are produced by enzymatic conversion of starch. They have a cyclic structure that is hydrophobic on the inside and hydrophilic on the outside. Due to the amphiphilic nature of the ring, cyclodextrins are known to enhance the solubility and bioavailability of hydrophobic compounds.

[0073] As shown in Fig.1, cyclodextrins are cyclic oligosaccharides containing 6 (α-cyclodextrin), 7 (β-cyclodextrin), and 8 (γ-cyclodextrin) glucopyranose monomers connected via α-1,4-glycosidic bonds. α-Cyclodextrin, β-Cyclodextrin and γ-Cyclodextrin are natural products resulting from microbial degradation of starch. The outer surface of donut-shaped cyclodextrin molecules is hydrophilic, bearing numerous hydroxyl groups, but their central cavity is somehow lyophilic (Kurkov, S.V., Loftsson, T., 2013. Cyclodextrins. Int J Pharm 453, 167-180; Loftsson, T., Brewster, M.E., 1996. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization.Journal of Pharmaceutical Sciences 85, 1017-1025). In addition to the three natural cyclodextrins, numerous water-soluble cyclodextrin derivatives have been synthesized and tested as drug carriers. Including cyclodextrin polymers (Stella, V.J., He, Q., 2008

Cyclodextrins. Tox. Pathol. 36, 30-42).

[0074] Cyclodextrins enhance the solubility and bioavailability of hydrophobic compounds. In aqueous solutions, cyclodextrins form inclusion complexes with many drugs by taking a drug molecule, or more commonly a lyophilic group of molecules, into the central cavity. This property is used as a drug formulation and for the purpose of drug delivery. The formation of drug/cyclodextrin inclusion complexes, their effect on the physicochemical properties of drugs, their effect on the ability of drugs to penetrate biomembranes, and the use of cyclodextrins in pharmaceuticals is reviewed (Loftsson, T., Brewster, M.E., 2010

Pharmaceutical applications of cyclodextrins: basic science and product development. Journal of Pharmacy and Pharmacology 62, 1607-1621; Loftsson, T., Brewster, M.E., 2011. Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes." J. Pharm. Pharmacol. 63, 1119-1135; Loftsson, T., Järvinen, T., 1999. Cyclodextrins in ophthalmic drug delivery. Advanced Drug Delivery Reviews 36, 59-79).

[0075] Cyclodextrins and drug/cyclodextrin complexes can self-assemble in aqueous solutions to form nano- and micro-aggregates and micelle-like structures that can also solubilize poorly soluble pharmaceutical ingredients through non-inclusion complexation and micellar-like solubilization (Messner, M., Kurkov, S.V., Jansook, P., Loftsson, T., 2010. Self-assembled cyclodextrin aggregates and nanoparticles. Int J Pharm 387, 199-208). In general, the tendency of cyclodextrins to self-assemble and form aggregates increases after the formation of a drug/cyclodextrin complex, and aggregation increases with increasing concentration of the active pharmaceutical ingredient/cyclodextrin complex. In general, hydrophilic cyclodextrin derivatives, such as 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin, and their complexes are readily soluble in water. On the other hand, natural α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and their complexes have limited solubility in pure water or 129.5 ± 0.7, 18.4 ± 0.2 and 249.2 ± 0.2 mg/ml, respectively, at 25°C (Sabadini E., Cosgrovea T. and do Carmo Egídio F., 2006. Solubility of cyclomaltooligosaccharides (cyclodextrins) in H2O and D2O: a comparative study. Carbohydr Res 341, 270-274). It is known that their solubility increases somewhat with increasing temperature (Jozwiakowski, M. J., Connors, K. A., 1985. Aqueous solubility behavior of three cyclodextrins. Carbohydr. Res., 143, 51-59). Due to the limited solubility of their complexes, natural cyclodextrins most often exhibit Bs-type or Bi-type phase solubility diagrams (Brewster M.

E., Loftsson T., 2007, Cyclodextrins as pharmaceutical solubilizers. Adv. Comrade Deliv. Rev., 59, 645-666). It has been observed that the solubility of natural cyclodextrins can be reduced below their solubility in pure water after the formation of the active pharmaceutical ingredient/cyclodextrin complex (Fig.2) (Jansook, P., Moya-Ortega, M.D., Loftsson, T., 2010. Effect of self-aggregation of γ-cyclodextrin on drug solubilization. Journal of Inclusion Phenomena and Macrocyclic Chemistry 68, 229-236). A small concentration of dissolved active pharmaceutical ingredient/cyclodextrin complexes slows down the formation of nano- and microparticles containing active pharmaceutical ingredient/cyclodextrin complexes. Furthermore, other excipients, such as water-dissolved polymers used to stabilize nano- and microsuspensions, can form complexes with cyclodextrins and, therefore, further slow down the formation of the active pharmaceutical ingredient/cyclodextrin complex.

[0076] Previously, the applicants described the preparation and testing of cyclodextrin-based eye drops containing dexamethasone (Johannesson, G., Moya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. Acta Ophthalmologica 92, 550-556; Cyclodextrin for ophthalmic drug delivery, US Pat. 22, 2011; Thorsteinn Loftsson, US Pat Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery US Pat. No.8,999,953 (Apr.7, 2015)), dorzolamide (Johannesson, G., Moya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. Acta Ophthalmologica 92, 550-556; Gudmundsdottir, B.S., Petursdottir, D., Asgrimsdottir, G.M., Gottfredsdottir, M.S., Hardarson, S.H., Johannesson, G., Kurkov, S.V., Jansook, P., Loftsson, T., Stefansson, E., 2014. γ-Cyclodextrin nanoparticle eye drops with dorzolamide: effect on intraocular pressure. in Man. J. Pharmacol. Ther.30, 35-41), irbesartan (Muankaew, C., Jansook, P., Stefansson, E., Loftsson, T., 2014. Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: influence of pH and excipients. Int J Pharm 474, 80-90), telmisartan (C. Muankaew, P. Jansook, H.H. Sigurðsson, T. Loftsson, 2016, Cyclodextrin-based telmisartan ophthalmic suspension: Development for water-insoluble drugs. Int. J. Pharm.

507, 21-31) and cyclosporin A (S. Jóhannsdóttir, P. Jansook, E. Stefansson, T. Loftsson, 2015, Development of a cyclodextrin-based aqueous cyclosporin A eye drop formulation. Int. J. Pharm. 493(1-2), 86-95) in cyclodextrin nanoparticles. Studies show that nanoparticles increase the contact time of the drug with the ocular surface and the ocular bioavailability of drugs. The active pharmaceutical ingredient/cyclodextrin nano- and microparticles are not only retained on the ocular surface but also enhance the solubility of the drug in the aqueous tear fluid. Nano-microparticles composed of active pharmaceutical ingredient/γ-cyclodextrin complexes have been shown to be particularly effective drug carriers for topical delivery of the active pharmaceutical ingredient to the eye.

[0077] There are two approaches for preparing nano- and microparticles and making nano- and micro-structures, a top-down approach and a bottom-up approach. A top-down approach to the preparation of active pharmaceutical ingredient/cyclodextrin nanoparticles and microparticles typically involves grinding solid active pharmaceutical ingredient/cyclodextrin complexes to make nanoparticles and microparticles of the desired diameter. Top down can introduce surface defects and contamination. The bottom-up approach for the preparation of active pharmaceutical ingredient/cyclodextrin nanoparticles means the assembly of individual molecules or individual active pharmaceutical ingredient/cyclodextrin complexes into microparticles of the desired diameter. The bottom-up approach often leads to microparticle structures with fewer defects and a more homogeneous chemical composition.

[0078] Applicants have surprisingly discovered a bottom-up preparation of drug/cyclodextrin nanoparticles that can be achieved with or without the presence of stabilizing polymers. According to the claimed process, the drug and cyclodextrin are suspended in an aqueous vehicle, such as an aqueous vehicle for eye drops, and heated. At high temperature, active compounds as well as cyclodextrin and other pharmaceutical excipients are completely or almost completely dissolved in aqueous media and the concentration of drug/cyclodextrin complex and excipient/cyclodextrin complex is at a much lower temperature than ambient temperature. The warm solution is then cooled at a predetermined rate to promote the formation of drug/cyclodextrin complex particles less than about 100 µm in diameter. Particle diameter can also be controlled by heating and cooling cycles and the presence of stabilizing polymers in aqueous media. To prevent or substantially inhibit or reduce degradation of the drug and/or excipient, excessive heating of the substrate followed by rapid cooling to room temperature is avoided.

[0079] Under controlled heating/cooling conditions, the aqueous solution comprising the cyclodextrin is heated at a temperature and duration of time to limit the formation of degradation products, or sedimentation. The initial aqueous solution optionally further comprises a drug active agent and/or a stabilizing polymer. During the heating cycle, the initial milky white solution of cyclodextrin turns into a clear solution. Heating is achieved by any process or means known to those skilled in the art. In preferred embodiments, heating is achieved with an autoclave. For example, the autoclave may be cycled for 20 to about 30 minutes at a temperature of about 90°C to about 120°C.

[0080] In an exemplary embodiment, under controlled heating/cooling conditions, an aqueous solution comprising cyclodextrin is heated at a temperature and time to limit the formation of degradation products, or sedimentation. The initial aqueous solution optionally further comprises an active pharmaceutical ingredient and/or a stabilizing polymer. During the heating cycle, the initial milky white cyclodextrin solution turns into a clear solution. Heating is achieved by any process or means known to those skilled in the art. In preferred embodiments, heating is achieved by autoclaving or steam duplication reactors. For example, an autoclave may be cycled for 10 to 30 minutes at a temperature of about 121°C.

[0081] The heated solution is then cooled at a sufficient rate to produce a drug/cyclodextrin complex less than about 100 µm in diameter. After cooling, the drug/cyclodextrin complex is precipitated to form the desired microsuspension. The microsuspension comprises about 70% to about 99% of the drug in the microparticles and about 1% to about 30% of the drug in the nanoparticle eye drop vehicle. The microparticles have an average diameter of about 1 µm to about 100 µm. It is possible for the average diameter of the microparticles to be in the range of about 1 µm to about 20 µm, about 1 µm to about 25 µm, about 1 µm to about 10 µm, or about 2 µm to about 5 µm. In an exemplary embodiment, the microsuspension includes about 80% of the drug in microparticles with an average diameter of about 1 µm to about 10 µm, and about 20% of the drug in nanoparticles.

[0082] In one embodiment, the heated solution is then cooled at a sufficient rate to produce aggregates of the drug/cyclodextrin complex less than about 100 µm in diameter. After cooling, the drug/cyclodextrin complex is precipitated to form the desired microsuspension. The microsuspension comprises about 40% to about 99% of the drug in microparticles and about 1% to about 60% of the drug in nanoparticles or water-soluble drug/cyclodextrin complexes. The microparticles have an average diameter of about 1 µm to about 100 µm. It is possible for the average diameter of the microparticles to be in the range of about 1 µm to about 20 µm, about 1 µm to about 25 µm, about 1 µm to about 10 µm, or about 2 µm to about 5 µm. In an exemplary embodiment, the microsuspension includes about 80% of the drug in microparticles with an average diameter of about 1 µm to about 10 µm, and about 20% of the drug in nanoparticles.

[0083] Microsuspensions prepared according to the protected procedure have about a 10-fold to 100-fold increase in the drug concentration of the dissolved active agent compared to microsuspensions prepared according to known procedures in the form of nanoparticles dissolved in water, individual drug/cyclodextrin complexes and dissolved drug molecules. For example, known compositions of dexamethasone include a concentration of dexamethasone of about 1 mg/mL with only 0.1 mg/mL in solution. However, a dexamethasone/cyclodextrin composition prepared according to the claimed process may comprise a concentration of dexamethasone of about 15 mg/mL with about 4 mg/mL being in solution.

[0084] In a preferred embodiment, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cydodextrin, or combinations thereof.

[0085] In a particularly preferred embodiment, the cyclodextrin is γ-cyclodextrin. In fact, γ-cyclodextrin has a higher solubility in water than α-cyclodextrin and β-cyclodextrin. Furthermore, γcyclodextrin is prone to hydrolysis to glucose and maltose subunits by α-amylase in the tear fluid and gastrointestinal tract.

[0086] The amount of cyclodextrin in the ophthalmic composition according to this disclosure can be from 1 to 25%, more specifically 5 to 20%, more specifically 10 to 18%, even more specifically 12 to 16 wt.%, of cyclodextrin in relation to the volume of the composition.

[0087] In addition to cyclodextrin, the ophthalmic composition according to this disclosure may further comprise a water-soluble cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, α-cyclodextrin sulfobutyl ether, β-cyclodextrin sulfobutyl ether, γ-cydodextrin sulfobutyl ether, methylated α-cyclodextrin, βcyclodextrin, methylated γ-cydodextrin, and their combinations. A water-soluble cyclodextrin derivative in particular can be used to further enhance the solubility of the active pharmaceutical ingredient, ie. the amount of active pharmaceutical ingredient dissolved in that composition.

Active pharmaceutical ingredient

[0088] The composition according to the present disclosure comprises an active pharmaceutical ingredient.

[0089] An active pharmaceutical ingredient may be labeled as a "drug". In the context of the present disclosure, the active pharmaceutical ingredient is an ophthalmic drug, ie. a compound that exhibits a therapeutic effect when administered in sufficient quantity to a patient suffering from an eye condition.

[0090] The active pharmaceutical ingredient is dexamethasone.

[0091] The concentration of the active pharmaceutical ingredient in the ophthalmic composition according to this disclosure can be from about 0.1 mg/mL to about 100 mg/mL, more specifically from about 1 mg/mL to about 100 mg/mL, more specifically from about 1 mg/mL to about 50 mg/mL, even more specifically from about 1 mg/mL to about 20 mg/mL, even more specifically from about 5 mg/mL to about 25 mg/mL, more specifically and further from about 10 mg/mL to about 20 mg/mL.

[0092] In exemplary embodiments, the active pharmaceutical ingredient (ie, drug) is present in the initial aqueous solution at a concentration of about 1 mg/mL to about 100 mg/mL. It is still possible to obtain the desired final concentration of the active pharmaceutical ingredient/cyclodextrin complex with an initial active pharmaceutical ingredient concentration of about 1 mg/mL to about 50 mg/mL and about 1 mg/mL to about 20 mg/mL.

[0093] In other exemplary embodiments, the active pharmaceutical ingredient is present in the initial aqueous solution at a concentration of about 0.01 mg/mL to about 10 mg/mL.

[0094] The compositions according to the present disclosure can have about a 10-fold to about a 100-fold increase in the concentration of dissolved active pharmaceutical ingredient compared to compositions prepared according to known methods.

[0095] More specifically, 60 to 95 wt.%, even more specifically 70 to 90 wt.%, of the active pharmaceutical ingredient in that composition can be in the form of a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0096] Even more specifically, 5 to 40 wt.%, more specifically 10 to 30 wt.%, of the active pharmaceutical ingredient in that composition can be in dissolved form. Dissolved form includes uncomplexed active pharmaceutical ingredient dissolved in liquid phase and complexes of active pharmaceutical ingredient and cyclodextrin dissolved in liquid phase as well as water-soluble nanoparticles consisting of drug/cyclodextrin complex aggregates.

[0097] Preferably, 0% to 0.5 wt.% of the active pharmaceutical ingredient in that composition may be in uncomplexed solid form. As such, the composition of the present disclosure may be substantially free of solid unaggregated particles of the active pharmaceutical ingredient.

[0098] In one embodiment, the microsuspension may comprise about 70% to about 99% of the active pharmaceutical ingredient in microparticles and about 1% to about 30% of the active pharmaceutical ingredient in nanoparticles. More specifically, the microsuspension may comprise about 80% of the active pharmaceutical ingredient in microparticles having a diameter of about 1 µm to about 10 µm, and about 20% of the active pharmaceutical ingredient in nanoparticles.

[0099] In another embodiment, the microsuspension may comprise about 40% to about 99% of the active pharmaceutical ingredient in microparticles and about 1% to about 60% of the active pharmaceutical ingredient in nanoparticles or water-soluble active pharmaceutical ingredient/cyclodextrin complexes.

More specifically, the microsuspension may comprise about 80% to about 90% of the active pharmaceutical ingredient in microparticles of about 1 µm to about 10 µm in diameter, and about 10% to about 20% of the active pharmaceutical ingredient in nanoparticles or water-soluble active pharmaceutical ingredient/cyclodextrin complexes.

Polymer

[0100] The composition of the present disclosure may further comprise a polymer.

[0101] More specifically, said polymer may be a water-soluble polymer. Furthermore, said polymer may be a viscosity-enhancing polymer. The term "viscosity-enhancing polymer" is intended to mean a polymer that increases the viscosity of a liquid. That polymer increases the viscosity of the composition according to this disclosure. This increase in viscosity leads to increased physical stability of the composition. As such, the composition is less prone to sedimentation of the solid complex when comprising the polymer. That polymer can therefore be considered a polymer stabilizer.

[0102] More specifically, the polymer may be a surface-active polymer. The term "surfactant polymer" is intended to mean a polymer that exhibits surfactant properties. Surfactant polymers may, for example, comprise hydrophobic chains grafted onto a hydrophilic polymer backbone; hydrophilic chains grafted onto a hydrophobic backbone; or alternating hydrophilic and hydrophobic segments. The first two types are called graft copolymers and the third type is called block copolymer.

[0103] In one embodiment, the ophthalmic composition according to the present disclosure comprises a polymer selected from the group consisting of polyoxyethylene fatty acid ester; polyoxyethylene alkylphenyl ether; polyoxyethylene alkyl ether; a cellulose derivative such as alkyl cellulose, hydroxyalkyl cellulose and hydroxyalkyl alkylcellulose; a carboxyvinyl polymer such as a carbomer, for example Carbopol 971 and Carbopol 974; polyvinyl polymer; polyvinyl alcohol; polyvinylpyrrolidone; copolymer of polyoxypropylene and polyoxyethylene; Tyloxapol; and their combinations.

[0104] Examples of suitable polymers include, but are not limited to, polyethylene glycol monostearate, polyethylene glycol distearate, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyoxyethylene lauryl ether, polyoxyethylene octyldodecyl ether, polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, polyoxyethylene oleyl ether, sorbitan ether, polyoxyethylene hexadecyl ether (eg, ketomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (eg, Tween 20 and Tween 80 (ICI Specialty Chemicals)); polyethylene glycols (eg, Carbowax 3550 and 934 (Union Carbide)), polyoxyethylene stearate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, cellulose, polyvinyl alcohol (PVA), poloxamers (eg, Pluronics F68 and FI08, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (eg, Tetronic 908, also known as Poloxamine 908, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation), Tritons X-200, which is an alkyl aryl polyether sulfonate (Rohm and Haas); PEG-derivatized phospholipid, PEG-derivatized cholesterol, PEG-derivatized cholesterol derivative, PEG-derivatized vitamin A, PEG-derivatized vitamin E, random copolymers of vinyl pyrrolidone and vinyl acetate, random copolymers of vinyl pyrrolidone and vinyl acetate, combinations thereof and the like.

[0105] Particularly preferred examples of polymers according to the present disclosure are tyloxapol and the copolymer polyoxypropylene and polyoxyethylene.

[0106] More particularly, the copolymer of polyoxypropylene and polyoxyethylene may be a triblock copolymer comprising a hydrophilic block-hydrophobic block configuration.

[0107] In one embodiment, the composition of the present disclosure comprises a polymer that is a poloxamer. Poloxamers may include any type of poloxamer known in the art. Poloxamers include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, poloxamer 105 benzoate and poloxamer 182 dibenzoate. Poloxamers are also labeled with their trade name Pluronic such as Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F 108, Pluronic F 108, Pluronic F 108, Pluronic F 108NF, Pluronic F 127, Pluronic F 127 NF, Pluronic F 127, Pluronic F 127, Pluronic F 38, Pluronic F 38, Pluronic F 68, Pluronic F 77, Pluronic F 87, Pluronic F 88, Pluronic F 98, Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L 35, Pluronic L 43, Pluronic L 44, Pluronic L 61, Pluronic L 62, Pluronic L 62 LF, Pluronic L 62D, Pluronic L 64, Pluronic L 81, Pluronic L 92, Pluronic L 44, Pluronic N 3, Pluronic P 103, Pluronic P 104, Pluronic P 105, Pluronic P 123, Pluronic P 65, Pluronic P 84, Pluronic P 85, their combinations and similar.

[0108] Particularly useful polymers as stabilizers are poloxamers. Poloxamers may include any type of poloxamer known in the art. Poloxamers include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, poloxamer 105 benzoate and poloxamer 182 dibenzoate. Poloxamers are also labeled by their trade name Pluronic such as Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F 108 Cast Solid Surfacta, Pluronic F 108 NF, Pluronic F 108 Pastille, Pluronic F 108NF Prill Poloxamer 338, Pluronic F 108 127, Pluronic F 127 NF, Pluronic F 127 NF 500 BHT Prill, Pluronic F 127 NF Prill Poloxamer 407, Pluronic F 38, Pluronic F 38 Pastille, Pluronic F 68, Pluronic F 68 Pastille, Pluronic F 68 LF Pastille, Pluronic F 68 NF, Pluronic F 68 NF Prill Poloxamer 188, Pluronic F 77, Pluronic F 77 Mikropastille, Pluronic F 87, Pluronic F 87 NF, Pluronic F 87 NF Prill Poloxamer 237, Pluronic F 88, Pluronic F 88 Pastille, Pluronic F 98, Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L 35, Pluronic L 43, Pluronic L 44 NF Poloxamer 124, Pluronic L 61, Pluronic L 62, Pluronic L 62 LF, Pluronic L 62D, Pluronic L 64, Pluronic L 81, Pluronic L 92, Pluronic L44 NF INH surfactant Poloxamer 124 View, Pluronic N 3, Pluronic P 103, Pluronic P 104, Pluronic P 105, Pluronic P 123 Surfactant, Pluronic P 65, Pluronic P 84, Pluronic P 85, their combinations and similar ones.

[0109] Another polymeric stabilizer compatible with the compositions and methods described herein is tyloxapol. In preferred embodiments, the stabilizer and co-solvent is tyloxapol, which is a 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane.

[0110] Solutions and microsuspensions prepared according to applicants' process optionally include further additives. For example, it is contemplated that the solution and/or microsuspension further comprises ethylenediaminetetraacetic acid (EDTA). EDTA can be used, for example, to reduce degradation or as a stabilizer. It is also contemplated that the solution and/or microsuspension is isotonic, for example, with the addition of sodium chloride.

[0111] In an exemplary embodiment, EDTA can be the disodium salt of ethylenediaminetetraacetic acid.

[0112] According to one method, the drug active agent and at least one cyclodextrin are suspended in an aqueous eye drop vehicle to provide a milky suspension. The suspension is then heated for a sufficient period at a sufficient temperature until both the drug and the cyclodextrin dissolve in the aqueous eye drop solution, and no degradation product is formed. Once the drug and cyclodextrin dissolve, the milky suspension turns into an essentially clear solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin microparticle complex.

[0113] In another embodiment, the active agent drug, at least one cyclodextrin, and at least one polymer are suspended in an aqueous eye drop vehicle to provide a milky suspension. This suspension is then heated for a sufficient period of time at a sufficient temperature until the drug, cyclodextrin, and polymer dissolve in the aqueous eye drop solution, and no degradation product is formed. When the drug, cyclodextrin, and polymer dissolve, the milky suspension turns into an essentially clear solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the drug/cyclodextrin/microparticle polymer complex. In this alternative embodiment, the drug/cyclodextrin/polymer complex comprises a polymeric protective layer.

[0114] In an alternative process, at least one cyclodextrin is suspended in an aqueous eye drop vehicle to provide a milky suspension. The cyclodextrin suspension is heated for a sufficient period at a sufficient temperature until the cyclodextrin dissolves in the aqueous eye drop solution. The active agent drug is added to the heated aqueous suspension, stirring the solution while the drug dissolves in the solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the microparticulate drug/cyclodextrin complex.

[0115] In yet another process, cyclodextrin and at least one polymer are suspended in an aqueous eye drop vehicle to provide a milky suspension. Once the cyclodextrin and polymer are dissolved, the milk suspension turns into an essentially clear solution. The active agent drug is added to the heated aqueous suspension, stirring the solution while the drug dissolves in the solution. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the microparticulate drug/cyclodextrin/polymer complex. The resulting drug/cyclodextrin/polymer complex includes a polymeric protective layer.

[0116] In another process, at least one polymer and drug are suspended in an aqueous eye drop vehicle to provide a milky suspension. In another container, at least one cyclodextrin is suspended in water to provide a milky suspension. Both suspensions are heated for a sufficient period of time at a sufficient temperature until the cyclodextrin solution becomes clear, wherein the polymer/drug suspension is still a milky suspension and does not form (essentially does not form) a degradation product. A cyclodextrin solution is added to the polymer/drug phase and the mixture becomes clear as the drug dissolves and the solution is stirred for a sufficient period at the same temperature. The resulting solution is cooled at a rate sufficient to produce a microsuspension comprising the microparticulate drug/cyclodextrin complex.

[0117] The polymer that can be introduced into the composition according to this disclosure can exhibit an average molecular weight of 2,000 g/mol or more, more specifically an average molecular weight of 2,000 to 50,000 g/mol, more specifically 5,000 to 25,000 g/mol, even more specifically 9,000 to 15,000 g/mol.

[0118] The amount of polymer in that composition according to this disclosure can be 0.5 to 5%, more specifically 1 to 4%, even more specifically 2 to 3%, even more specifically 2.2 to 2.8 wt.% of polymer in relation to the volume of the composition.

[0119] When the composition comprises a polymer, the viscosity of the composition may be from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0120] Part of the polymer introduced into the composition according to this disclosure may be contained in solid complexes of the active pharmaceutical ingredient and cyclodextrin. As such, some polymers may be taken up within the solid complex and/or some of the polymer may be coated on the surface of the solid complex.

The microsuspension may thus comprise a drug/cyclodextrin/microparticle polymer complex. Said drug/cyclodextrin/polymer complex may include a polymeric protective layer.

Ophthalmologically acceptable foundation

[0121] The composition according to the present disclosure comprises an ophthalmologically acceptable base.

[0122] The term "ophthalmologically acceptable base" is intended to mean a base suitable for ophthalmological application of the composition. An ophthalmologically acceptable base is preferably a liquid. Ophthalmologically acceptable substrate can significantly contain water. More specifically, the ophthalmically acceptable base does not include any solvent other than water. An ophthalmologically acceptable base can therefore correspond to the aqueous vehicle of the eye drops.

[0123] According to the preferred method of realization, the ophthalmologically acceptable base comprises water and optionally an additive selected from the group consisting of a preservative, a stabilizer, an electrolyte, a buffer, and their combinations.

[0124] More specifically, the ophthalmologically acceptable base may include a preservative. A preservative may be used to limit bacterial proliferation in the composition.

[0125] Suitable examples of preservatives are sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, vremerosal, phenylmercury acetate, phenylmercury nitrate, methylparaben, phenylethyl alcohol, and combinations thereof. Preferably, the preservative is benzalkonium chloride.

[0126] The amount of preservatives in the composition according to this disclosure may be 0 to 1%, more specifically 0.001 to 0.5%, even more specifically 0.005 to 0.1%, even more specifically 0.01 to 0.04 wt.% of the preservative relative to the volume of the composition.

[0127] More specifically, the ophthalmologically acceptable base may comprise a stabilizer. A stabilizer may be used to reduce degradation or stabilize the composition during storage.

[0128] An example of a suitable stabilizer is disodium edetate.

[0129] The amount of stabilizer in that composition according to this disclosure can be 0 to 1%, more specifically 0.01 to 0.5%, even more specifically 0.08 to 0.2 wt.% of the stabilizer in relation to the volume of the composition.

[0130] More specifically, the ophthalmologically acceptable support may comprise an electrolyte. In particular, an electrolyte can be used to make the composition isotonic.

[0131] Examples of suitable electrolytes include sodium chloride, potassium chloride, and combinations thereof.

Preferably, the electrolyte is sodium chloride.

[0132] The amount of electrolyte in that composition according to this disclosure may be 0 to 2%, more specifically 0.1 to 1.5%, even more specifically 0.5 to 1 wt.% of electrolyte in relation to the volume of the composition.

Impurities

[0133] The composition according to the present disclosure can exhibit a significantly low concentration of impurities. A small amount of impurities in that composition according to this disclosure originates from the specific preparation process described further below, more specifically the specific heating and cooling phases applied in the preparation process.

[0134] Accordingly, the composition according to the present disclosure may comprise less than 2%, more specifically less than 1%, even more specifically less than 0.8 wt.% of impurities relative to the mass of the active pharmaceutical ingredient.

[0135] The term "impurity" is intended to mean a product that is not intentionally introduced into the composition of the present disclosure but is instead generated in situ during the manufacture of the composition. As such the term "impurity" includes any product other than active pharmaceutical ingredient, cyclodextrin, complex of active pharmaceutical ingredient and cyclodextrin, polymer, water, preservative, stabilizer, and electrolyte as previously defined herein. Impurities usually correspond to a by-product or degradation product of the active pharmaceutical ingredient. The amount of impurities in that composition can be determined by conventional analytical techniques including, for example, liquid chromatography, mass spectrometry and/or NMR. The amount of impurities can be measured immediately after, for example less than 24 hours after, preparation of the composition or after storage of the composition, for example up to 2 years of storage of the composition, at 25°C.

[0136] Surprisingly, applicants have observed that compositions according to this disclosure containing specific active pharmaceutical ingredients are particularly prone to forming impurities when their aqueous solutions or suspensions are heated in the presence of cyclodextrins, for example γ-cydodextrin, at a temperature above 120°C. However, negligible amounts of impurities were obtained when the compositions were prepared according to the process of this disclosure described below.

[0137] Accordingly, when the active ingredient is dexamethasone, the composition of the present disclosure may comprise less than 0.5%, more specifically less than 0.3%, more specifically less than 0.2%, dexamethasone enol aldehyde (ie, mixtures of Z and E isomers) by weight of dexamethasone.

[0138] Dexamethasone enol aldehydes represent dehydrated dexamethasone with the following structures:

[0139] Further, when the active ingredient is dexamethasone, the composition according to the present disclosure may comprise less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone relative to the weight of dexamethasone.

[0140] 16,17-unsaturated dexamethasone is dehydrated dexamethasone with the following structure:

[0141] More specifically, when the active ingredient is dexamethasone, the composition according to this disclosure may comprise less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2 wt.% of dehydrated dexamethasone, i.e. of dexamethasone enol aldehyde (ie, a mixture of Z and E isomers) and 16,17-unsaturated dexamethasone, relative to the mass of dexamethasone.

[0142] Dexamethasone is known to undergo base-catalyzed and photochemical degradation in aqueous solutions (E. M. Cohen, 1973, Dexamethasone. Analytical Profiles of Drug Substances, 2, 163-197) and the active pharmaceutical ingredient is known to undergo oxidative decomposition (R. E. Conrow, G. W. Dillow, L. Bian, L. Xue, O. Papadopoulou, J. K. Baker, B. S. Scott, 2002, Corticosteroid decomposition via a mixed anhydride. J. Org. 67, 6835-6836). The dexamethasone monograph in the European Pharmacopoeia (01/2014:0388) lists 11 impurities and degradation products and describes the procedure for their detection. The British Pharmacopoeia (2015, edition 19.0) has a monograph on dexamethasone eye drop suspension and lists 5 impurities and degradation products and a procedure for their detection. For maximum chemical stability in aqueous solutions, the pH of the dexamethasone eye drop suspension should be maintained between about 5.0 and about 6.0. It is believed that the major degradation product formed during the preparation of an aqueous suspension of eye drops containing cyclodextrin and sterilization of the eye drops in an autoclave includes 16,17-unsaturated dexamethasone and a mixture of E and Z isomers of dexamethasone enol aldehydes, formed by Mattox displacement via dehydration of dexamethasone (B. Chen, M. Li, M. Lin, G. Tumambac, A. Rustum, 2009, A comparative study of enol aldehyde formation from betamethasone, dexamethasone, beclomethasone and related compounds under acidic and alkaline conditions. Steroids, 74, 30-41). Due to steric hindrance in the case of dexamethasone, the major product is believed to be the Z isomer of dexamethasone enol aldehyde. This breakdown product is not listed in pharmacopoeias. Earlier, 16,17-unsaturated dexamethasone was detected in parenteral solutions of dexamethasone that were heated to about 75°C for about 10 days (M. Spangler, E. Mularz, 2001, A validated, stability-indicating method for the assay of dexamethasone in drug substance and drug product analyses, and the assay of preservatives in drug product. Chromatographia, 54, 329-334), which is also a dehydrated dexamethasone degradation product and since the authors did not analyze the product the authors probably detected enol aldehydes. Earlier, a Japanese group described those two enol aldehydes and 16-17 unsaturated products of betamethasone decomposition, both by acid catalysis (T. Hidaka, S. Huruumi, S. Tamaki, M. Shiraishi, H. Minato, 1980, Studies on betamethasone: behavior of betamethasone in acid or alkaline medium, photolysis and oxidation. Yakugaku Zasshi, 100, 72-80). The apparent activation energy for the rate of degradation of dexamethasone to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in aqueous γ-cyclodextrin is unusually high and, therefore, these degradation products are essentially not formed at ambient temperature. The presence of cyclodextrin in aqueous eye drops appears to promote dehydration of dexamethasone during autoclaving to form 16,17-unsaturated dexamethasone and a mixture of E and Z isomers of dexamethasone enol aldehyde.

[0143] In aqueous solutions, diclofenac is relatively stable at room temperature when protected from light and oxygen (R. Chadaha, N. Kashid, D. V. S. Jain, 2003, Kinetics of degradation of diclofenac sodium in aqueous solution determined by a calorimetric method. Pharmazie, 58, 631-635). Although βcyclodextrin has been shown to stabilize diclofenac in aqueous solutions at around pH 7, we have only observed that γcyclodextrin can accelerate degradation during autoclaving, causing intense staining of diclofenac aqueous solutions.

[0144] Here, applicants have surprisingly discovered that the proprietary process provides solutions and microsuspensions comprising active pharmaceutical ingredient/cyclodextrin complexes that are stable in aqueous solution. For example, the proprietary process provides a dexamethasone/γ-cyclodextrin eye drop solution in which very small amounts of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde are formed. Furthermore, this disclosure provides a diclofenac/ycyclodextrin solution in which no degradation or sedimentation product has been observed for at least 12 months. These aqueous eye drops containing γ-cyclodextrin also benefit from a 10- to 100-fold increase, in the case of dexamethasone about a 30-fold increase, in the concentration of the dissolved active pharmaceutical ingredient, and have the desired particle size to achieve maximum drug diffusion.

Composition of dexamethasone

[0145] According to a particularly preferred embodiment, the present disclosure provides an ophthalmic composition of dexamethasone comprising, in an ophthalmically acceptable carrier, a solid complex comprising dexamethasone and γ-cyclodextrin.

[0146] In one embodiment, the ophthalmic composition of dexamethasone according to this disclosure comprises less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde relative to the weight of dexamethasone.

[0147] In another embodiment, the dexamethasone ophthalmic composition of the present disclosure comprises a polymer as previously defined herein. The viscosity of the mentioned ophthalmic composition of dexamethasone can be from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0148] Again in another embodiment, the ophthalmic composition of dexamethasone according to this disclosure comprises less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde relative to the weight of dexamethasone; the dexamethasone ophthalmic composition of the present disclosure comprises a polymer; and the viscosity of the dexamethasone ophthalmic composition is from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0149] The concentration of dexamethasone in the ophthalmic composition according to the present disclosure can be from 10 mg/mL to 20 mg/mL. As such, the amount of dexamethasone in the composition according to the present disclosure is much higher than known dexamethasone compositions which include a dexamethasone concentration of about 1 mg/mL with about 0.1 mg/mL in solution. More specifically, the concentration of dexamethasone in an ophthalmic composition according to the present disclosure may be about 15 mg/mL, with about 4 mg/mL being in solution.

[0150] More specifically, 60 to 95 wt.%, even more specifically 70 to 90 wt.%, of dexamethasone in that composition can be in the form of a solid complex of dexamethasone and γ-cyclodextrin.

[0151] More specifically, 5 to 40 wt.%, more specifically 10 to 30 wt.%, of dexamethasone in that composition can be in dissolved form. Dissolved form includes uncomplexed dexamethasone dissolved in the liquid phase, complexes of dexamethasone and cyclodextrin dissolved in the liquid phase, and water-soluble nanoparticles consisting of dexamethasone/cyclodextrin complex aggregates.

[0152] Preferably, 0% to 0.5% by weight of the dexamethasone in the composition may be in uncomplexed solid form. As such, the composition of the present disclosure may be substantially free of unaggregated dexamethasone particles.

[0153] In one embodiment, the microsuspension may comprise about 70% to about 99% dexamethasone in microparticles and about 1% to about 30% dexamethasone in nanoparticles. More particularly, the microsuspension may comprise about 80% dexamethasone in microparticles having a diameter of about 1 µm to about 10 µm, and about 20% dexamethasone in nanoparticles.

[0154] In another embodiment, the microsuspension may comprise 40% to 99% dexamethasone in microparticles and about 1% to about 60% dexamethasone in nanoparticles or water-soluble dexamethasone/γ-cyclodextrin complexes. More specifically, the microsuspension may comprise about 80 to 90% of the dexamethasone in microparticles of about 1 µm to about 10 µm in diameter, and about 10 to 20% of the dexamethasone in nanoparticles or water-soluble dexamethasone/γ-cyclodextrin complexes.

[0155] The amount of γ-cyclodextrin in the ophthalmic composition of dexamethasone can be from 1 to 25%, more specifically 5 to 20%, more specifically 10 to 18%, even more specifically 12 to 16 wt.% of γ-cyclodextrin in relation to the volume of the composition.

[0156] In addition to γ-cydodextrin, the ophthalmic composition according to the present disclosure may further comprise α-cyclodextrin, β-cyclodextrin and/or a water-soluble cyclodextrin derivative as previously defined.

[0157] The dexamethasone ophthalmic composition of the present disclosure includes ophthalmically acceptable excipients as previously defined.

[0158] According to the preferred method of realization, the ophthalmologically acceptable base includes water and optionally an additive selected from the group consisting of a preservative, a stabilizer, an electrolyte, a buffer, and their combinations, as previously defined.

[0159] In a particularly preferred embodiment, the ophthalmic composition of dexamethasone comprises:

- 1 to 2% dexamethasone, for example 1.5% dexamethasone;

- 12 to 16% γ-cydodextrin, for example 14% γ-cyclodextrin;

- 2.2 to 2.8% polymer, for example 2.5% poloxamer;

- 0 to 0.2% stabilizer, for example 0.1% disodium edetate;

- 0 to 1% electrolyte, for example 0.57% sodium chloride; and

- water;

where % represent wt.% in relation to the volume of the composition.

A method of preparing an ophthalmic composition according to this disclosure

[0160] The compositions according to this disclosure can be obtained or have been obtained by the following methods. All of the embodiments, preferred embodiments, and specific examples set forth in the preceding sections apply equally to the processes of this disclosure and the compositions obtained by the processes of this disclosure.

[0161] In the first embodiment, the procedure for preparing the ophthalmic composition includes stages

a) suspending the active pharmaceutical ingredient and cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension at a temperature T1 lower than 120°C for a time t until the active pharmaceutical ingredient and the cyclodextrin are substantially dissolved in the ophthalmologically acceptable medium; and c) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0162] In the process according to the first embodiment, the active pharmaceutical ingredient and the cyclodextrin can be suspended in an ophthalmologically acceptable vehicle to provide a milky suspension. This suspension may then be heated for a sufficient period of time at a sufficient temperature until both the active pharmaceutical ingredient and the cyclodextrin are dissolved in the ophthalmically acceptable medium, and no degradation product is formed. Once the active pharmaceutical ingredient and the cyclodextrin are dissolved, the milky suspension may turn into a substantially clear solution. The resulting solution can then be cooled at a rate sufficient to produce a microsuspension comprising the solid active pharmaceutical ingredient/cyclodextrin complex.

[0163] In another embodiment, the procedure for preparing the ophthalmic composition comprises the stages of a) suspending cyclodextrin in an ophthalmologically acceptable medium in order to form a suspension;

b) heating the suspension until the cyclodextrin is substantially dissolved in the ophthalmologically acceptable medium;

c) adding the active pharmaceutical ingredient in solid form to the solution from step b) at a temperature T1 lower than 120°C and heating the mixture at a temperature T1 lower than 120°C for a time t until the active pharmaceutical ingredient is substantially dissolved in the ophthalmically soluble base; and

d) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0164] In another embodiment, the cyclodextrin may be suspended in an ophthalmologically acceptable vehicle to provide a milky suspension. The cyclodextrin suspension can be heated for a sufficient period of time at a sufficient temperature until the cyclodextrin is dissolved in an ophthalmically acceptable medium. The active pharmaceutical ingredient can be added in solid form to a heated aqueous solution, whereby the solution is stirred. Heating can be carried out for a sufficient period at a sufficient temperature until the active pharmaceutical ingredient is dissolved in the ophthalmologically acceptable medium, and no degradation product is formed. The resulting solution can be cooled at a rate sufficient to produce a microsuspension comprising a solid active pharmaceutical ingredient/cyclodextrin complex.

[0165] In the third embodiment, the process of preparing the ophthalmic composition comprises the stages of a) suspending the active pharmaceutical ingredient in an ophthalmically acceptable base to form a suspension and heating said suspension until the active pharmaceutical ingredient essentially dissolves in the ophthalmically soluble base;

b) suspending the cyclodextrin in an ophthalmically acceptable medium to form a suspension and heating said suspension until the cyclodextrin is substantially dissolved in the ophthalmically acceptable medium;

c) mixing the composition from phases a) and b) at a temperature T1 lower than 120°C and heating the mixture at a temperature T1 lower than 120°C during time t; and

d) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of the active pharmaceutical ingredient and cyclodextrin.

[0166] In the third embodiment, the active pharmaceutical ingredient can be suspended in an ophthalmologically acceptable medium that does not contain cyclodextrin. The resulting suspension may have a milky appearance. Separately, the cyclodextrin can be suspended in an ophthalmically acceptable vehicle that does not contain the active pharmaceutical ingredient. The resulting suspension may have a milky appearance. The two suspensions can be heated or sterilized, for example, by heating in an autoclave at 121°C for 20 minutes. Then the two suspensions or warm solutions can be mixed together and the mixture can be heated until a complex of the active pharmaceutical ingredient and the cyclodextrin is formed, and a degradation product is formed. The resulting solution can be cooled at a rate sufficient to produce a microsuspension comprising a solid active pharmaceutical ingredient/cyclodextrin complex.

[0167] The ophthalmic composition obtained by the procedures according to the first, second and third methods of realization can include less than 2%, more specifically less than 1%, even more specifically less than 0.8 wt.% of impurities in relation to the mass of the active pharmaceutical ingredient.

[0168] The present disclosure also provides methods of preparing dexamethasone ophthalmic compositions according to the present disclosure.

[0169] Accordingly, in the fourth way of realization, the procedure for preparing the ophthalmic composition, which includes the stages:

a) suspending dexamethasone and γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension at a temperature T1 lower than 120°C for a time t until the dexamethasone and γ-cyclodextrin are substantially dissolved in the ophthalmologically acceptable medium; and

c) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0170] In the fifth way of realization, the procedure for preparing the ophthalmic composition includes the stages:

a) suspending γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension until the γ-cyclodextrin dissolves in an ophthalmologically acceptable medium; c) adding dexamethasone in solid form to the solution of step b) at a temperature T1 lower than 120°C and heating the mixture at a temperature T1 lower than 120°C for a time t until the dexamethasone is substantially dissolved in the ophthalmic acceptable medium; and

d) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0171] In the sixth embodiment, the process of preparing the ophthalmic composition comprises the stages of: a) suspending dexamethasone in an ophthalmically acceptable medium to form a suspension and heating said suspension until the dexamethasone is essentially dissolved in the ophthalmically acceptable medium;

b) suspending the γ-cyclodextrin in an ophthalmically acceptable medium to form a suspension and heating said suspension until the γ-cyclodextrin is substantially dissolved in the ophthalmically acceptable medium;

c) mixing the compositions from phases a) and b) at a temperature T1 lower than 120°C and heating the mixture at a temperature T1 lower than 120°C during time t; and

d) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin.

[0172] Ophthalmic compositions obtained by the procedures according to the third, fourth and fifth methods of realization can include less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2 wt.% of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde in relation to the mass of dexamethasone.

[0173] The heating phase of the processes according to this disclosure is performed at a temperature T1 lower than 120°C to avoid the formation of impurities. More specifically, the temperature T1 can be from 80 to 110°C, more specifically from 85 to 105°C, even more specifically from 90 to 100°C.

[0174] The heating phase of the methods according to this disclosure is performed during time t. More specifically, the heating time t is from 5 minutes to 2 hours, more specifically from 10 minutes to 1 hour, even more specifically from 15 to 30 minutes.

[0175] During the heating cycle, the active pharmaceutical ingredient and/or cyclodextrin are dissolved and a complex of the active pharmaceutical ingredient and cyclodextrin is formed. Heating is achieved by any process or means known to those skilled in the art. In preferred embodiments, the heating is achieved by an autoclave or steam duplication reactor.

[0176] The cooling phase of the methods of the present disclosure lowers the temperature of the composition from temperature T1 to temperature T2 in order to precipitate a solid complex of the active pharmaceutical ingredient and cyclodextrin. More specifically, the temperature T2 can be from 10 to 40°C, more specifically from 15 to 35°C, even more specifically from 20 to 30°C.

[0177] The cooling rate of the processes according to this disclosure can be performed by lowering the temperature T1 to the temperature T2 at a rate of 1 to 25°C/min, more specifically 2 to 20°C/min, more specifically 5 to 18°C/min.

[0178] Cooling can be achieved by any process or means known to those skilled in the art. In preferred embodiments, cooling is accomplished with an ice bath or a duplication reactor with a cooler.

[0179] In the procedures of some exemplary embodiments, for example, the first, second, third, fourth, fifth and sixth embodiments, the suspension from phase a) may further comprise a polymer as previously defined. In the processes of the third and sixth embodiments, the suspension from phase b) may further include a polymer as previously defined. When the initial suspension comprises a polymer, a portion of the polymer may be taken up within the solid complex and/or the surface of the complex may be partially coated with the polymer. A microsuspension obtained by the process of the present disclosure may thus comprise a microparticulate drug/cyclodextrin/polymer complex. Said drug/cyclodextrin/polymer complex may include a polymeric protective layer.

[0180] When the polymer is introduced into the initial suspension of the processes according to this disclosure, the ophthalmic composition obtained by said processes can exhibit a viscosity of 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP.

[0181] The viscosity of the compositions obtained by the methods according to the present disclosure is higher than that of the compositions obtained by known manufacturing methods. Without wishing to be bound by any theory, applicants believe that the application of a controlled cooling phase of the process, more specifically a cooling rate of 1 to 25°C/min, after the heating phase allows less polymer to be incorporated into the solid complex, and therefore more polymer is found in solution, thus increasing the viscosity of the formulation. Therefore, the original manufacturing process disclosed in this application allows obtaining new formulations of increased viscosity with similar amounts of polymer, cyclodextrin and active pharmaceutical ingredient, as in formulations from the prior art.

[0182] In the procedures of exemplary embodiments, for example, the first, second, third, fourth, fifth and sixth embodiments, the ophthalmologically acceptable substrate may include water and optionally an additive selected from the group consisting of a preservative, stabilizer, electrolyte, buffer, and combinations thereof.

[0183] In examples of procedures, for example, the first, second, fourth and fifth ways of realization, the ophthalmologically acceptable base from phase a) can include water and optionally an additive selected from the group consisting of a preservative, stabilizer, electrolyte, buffer, and their combinations.

[0184] In further examples of procedures, for example, the third and sixth methods of realization, the ophthalmologically acceptable base from phase a) can include only water and the ophthalmologically acceptable base from phase b) can include water and optionally an additive selected from the group consisting of a preservative, stabilizer, electrolyte, buffer, and their combinations.

[0185] In alternative methods of implementation, for example, the procedures from the third and sixth methods of implementation, the ophthalmologically acceptable base from phase b) can include only water, and the ophthalmologically acceptable base from phase a) can include water and optionally an additive selected from the group consisting of a preservative, stabilizer, electrolyte, buffer, and their combinations.

Uses of the composition according to this disclosure

[0186] Ophthalmic compositions according to this disclosure may be for use in the treatment of an eye condition, more specifically an anterior eye condition or a posterior eye condition, more specifically uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infection, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion. The compositions of the present disclosure may be particularly useful in the treatment of uveitis, macular edema, diabetic retinopathy, proliferative vitreoretinopathy (PVR), and vascular occlusions.

[0187] The dexamethasone ophthalmic composition of the present disclosure can more particularly be used to treat macular edema. In this case, the dexamethasone ophthalmic composition of the present disclosure can be topically applied to the eye in an amount of 1 drop of the composition three times a day. The amount of dexamethasone in said composition can be from 1 to 2%, more specifically 1.5 wt.% of dexamethasone in relation to the volume of the composition.

[0188] The compositions according to this disclosure do not need to be applied as frequently as the known topical dexamethasone compositions, i.e. 1 drop of the composition six times a day. In fact, due to the increased viscosity of the composition, the solid complexes of the composition according to this disclosure exhibit a longer contact time on the surface of the eye compared to known compositions that increase the bioavailability of the active pharmaceutical ingredient.

[0189] This disclosure also covers the use of the ophthalmic compositions of this disclosure in the form of eye drop solutions.

MEASUREMENT PROCEDURES

Diameter

[0190] The diameter of a particle, such as a solid complex of an active pharmaceutical ingredient and a cyclodextrin, may correspond to the D50 diameter of the particle. The diameter D50 is also known as the mean diameter or mean value of the particle size distribution. Diameter D50 corresponds to the value of the particle diameter at 50% in the cumulative distribution. For example, if D505 µm, then 50% of the particles in the sample are larger than 5 µm and 50% are smaller than 5 µm. The diameter D50 is usually used to represent the particle size of a group of particles.

[0191] The diameter and/or size of the particles or complex can be measured according to any method known to those skilled in the art. For example, the D50 diameter is measured by laser diffraction particle size analysis. In general, there are a limited number of techniques for measuring/estimating cyclodextrin/drug particle or complex diameter and/or size. More specifically, those skilled in the art know that physical properties (eg, particle size, diameter, average diameter, median particle size, etc.) are typically estimated/measured using such limited, commonly known techniques. For example, such known techniques are described in Int. J. Pharm. 493(2015), 86-95, above paragraph [00076]. In addition, such limited, known measurement/assessment techniques were known in the art as evidenced by other technical references, such as, for example, the European Pharmacopoeia (2.9.31 Particle size analysis by laser diffraction, Jan 2010), and Saurabh Bhatia, Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications, Chapter 2, Natural Polymer Drug Delivery Systems, PP.33-94, Springer, 2016.

[0192] For the particle size of complexes that include an active pharmaceutical ingredient other than dexamethasone, the particle size is measured by laser diffraction particle size analysis according to Pharm. Eur.2.9.31.

[0193] For particle size of complexes comprising dexamethasone, particle size is measured by laser diffraction particle size analysis according to Pharm. Eur.2.9.31 with the following parameters:

- System: Malvern Mastersizer 3000 with hydro MV atomizer

- Fraunhofer approximation

- Sprayer: water

- Refractive index of the diffuser: 1.33

- Measurement time: 1 second

- Background measurement time: 10 seconds

- Mixer speed: 1200 rpm

- Dimming range: 1-20%

- Model: standard

- Sample preparation: homogenization of eye drops by shaking

- Sample size: adding 0.5 ml eye drops to the atomizer

- Cleaning: rinsing twice with a sprayer (water) and starting the measurement, checking that the beam strength is less than 120 units in the first channels, and loading the background.

Viscosity

[0194] The viscosity of the composition corresponds to the dynamic viscosity of said composition. Viscosity is measured at 25°C with a Brookfield digital viscometer. The viscosity of the composition is measured immediately after, i.e. less than 24 hours after the preparation of the composition.

The percentage of the drug in the solid complex and the percentage of the dissolved drug

[0195] The amount of drug in the form of solid complexes and the amount of dissolved drug are obtained by centrifuging the composition at 6000 rpm at a temperature of 22-230C for 20-30 minutes.

[0196] The amount of dissolved drug corresponds to the amount of drug in the supernatant as measured by high performance liquid chromatography.

[0197] The percentage of the drug in the form of a solid complex is obtained by the following formula:

whereby

"total drug" represents the total amount of drug introduced into that composition in mg/mL; and "dissolved drug" represents the amount of drug in the supernatant in mg/mL.

[0198] The percentage of dissolved drug is obtained by the following formula:

% of dissolved drug = 100 - % of drug in solid complex

EXAMPLES

EXAMPLE 1

[0199] The composition of aqueous dexamethasone eye drops is as follows: dexamethasone (1.50%), γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), benzalkonium chloride (0.02%), disodium edetate (0.10%), sodium chloride (0.57%) in purified water, all in w/v %. Five different procedures are applied.

F1: dissolving or suspending the ingredients, including dexamethasone, in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes. The vials containing the essentially clear aqueous solution are removed from the autoclave, and become cloudy upon cooling to ambient temperature. Solid particles are analyzed by Fourier transform infrared

(FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) indicating that the solid particles comprise dexamethasone/γ-cyclodextrin complexes.

F2: dissolving or suspending the ingredients, including dexamethasone, in pure water and heating the mixture for 30 minutes to 90°C to form a clear solution. By further heating at 90°C for 15 minutes, the solution was allowed to cool and become cloudy at ambient temperature, reaching room temperature within 3 hours.

F3: dissolving or suspending pharmaceutical excipients in pure water, heating the mixture to 90°C to form a clear solution and then adding solid dexamethasone powder to the warm solution. Once the dexamethasone is dissolved (with stirring for 15 minutes), the solution is allowed to cool and become cloudy at ambient temperature, reaching room temperature within 3 hours.

F4: dissolving or suspending pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95°C, solid dexamethasone powder is added to the solution. Once the dexamethasone is dissolved (with stirring for 15 minutes), the solution is allowed to cool and become cloudy at ambient temperature, reaching room temperature over approximately 3 hours.

F5: dissolving or suspending pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95°C, solid dexamethasone powder is added to the solution. When the dexamethasone is dissolved (with stirring for 15 minutes) the solution cools rapidly to room temperature (within 20 minutes) and becomes cloudy on cooling.

F6: excipients are separated into two parts, A and B. In part A, all excipients except γ-cyclodextrin are dissolved in pure water at 80°C and in part B γ-cyclodextrin is suspended (or dissolved) separately in pure water at 80°C. Dexamethasone is added to the excipient mixture immediately before sterilization. The two parts of the mixture of excipients in water containing dexamethasone (part A) and γ-cyclodextrin suspended (or dissolved) in water (part B) were sterilized at 121°C for 15 minutes. After sterilization, sterile γ-cyclodextrin is added to the rest of the sterile excipients at 95°C. In other words, parts A and B are mixed up. After stirring for 15 minutes, the solution was rapidly cooled to room temperature (over 20 minutes) to form a cloudy suspension. F6 did not contain benzalkonium chloride.

TABLE 1

[0200] Results of the microparticle formation test. Mean value of three determinations ± standard deviation.

[0201] The results show that rapid cooling (F5) provides a microsuspension in which more than about 80% of the active pharmaceutical ingredient and γ-cyclodextrin are dissolved in the solid phase in the form of the active pharmaceutical ingredient/γ-cyclodextrin complex and in which most of the polymers are in aqueous solution (ie, they have the highest viscosity). F1 settles over time, but can redisperse with some agitation. However, F5 has little tendency to settle over time and quickly redisperses with stirring. Therefore, F5 shows a significantly higher physical stability than F1.

Example 2 (illustrative)

[0202] The composition of irbesartan aqueous eye drops is as follows: irbesartan (2.0%), γ-cyclodextrin (10.0%), HPMC (0.20%), tyloxapol (0.10%), benzalkonium chloride (0.02%), disodium edetate (0.10%), sodium chloride (0.50%) in purified water, all in w/v %. Three different procedures apply:

F7: dissolving or suspending the ingredients, including irbesartan, in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. The clear aqueous solution was allowed to cool to room temperature and become cloudy.

F8: dissolving or suspending pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95°C, solid irbesartan powder is added to the solution. Once the irbesartan has dissolved (15 minutes), the solution is allowed to cool and become cloudy at ambient temperature, reaching room temperature within 3 hours.

F9: dissolving or suspending pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95°C, solid irbesartan powder is added to the solution. When irbesartan dissolves (15 minutes) the solution cools rapidly to room temperature (in 20 minutes) and becomes cloudy.

[0203] For formulation F7, the formulation may have a solid drug fraction of 54%, a viscosity at 25°C (cP) of 4.36 and a mean particle size (µm) of 2.44.

EXAMPLE 3

[0204] Dehydration of dexamethasone during the preparation of aqueous dexamethasone eye drops described in example 1 (formulations F1, F2, F3, F4, F5 and F6) is determined by quantitative determination of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde in the eye drops after production.

Formulations F12, F13 and F14 were prepared as described in F1, i.e. by dissolving or suspending the ingredients, including dexamethasone, in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes. Essentially, vials of clear aqueous solution are removed from the autoclave and become cloudy after cooling to ambient conditions. The composition of F12 is identical to F1, but does not contain γ-cyclodextrin. F13 comprises dexamethasone and γ-cyclodextrin suspended in pure water. F14 comprises dexamethasone suspended in pure water. The effect of excipients and preparation procedures on the formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes is presented as the fraction (in %) of dexamethasone degraded to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes.

TABLE 2

[0205] The results presented in Table 2 show that the formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde is catalyzed by the presence of γ-cyclodextrin during heating in the autoclave, formulation F1 (includes all excipients) and F13 (includes γ-cyclodextrin but no other excipients). Much less 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde was formed in the aqueous eye drop formulation when γ-cyclodextrin was removed from the formulation (F12) or when the eye drops were prepared by heating to 90°C for 15 minutes (F2, F3 and F4). Little or no 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde were formed in the eye drops during storage at room temperature (22-23°C) for 12 months. During the formulation of F6 aqueous suspension of γ-cyclodextrin and separately aqueous suspension containing dexamethasone and all other ingredients except γ-cyclodextrin were autoclaved at 121°C for 15 minutes. After autoclaving, the two suspensions/solutions were cooled to 95°C before mixing and then further cooled to ambient temperature (see example 1). Only a minor amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde was formed in the aqueous eye drop formulation when dexamethasone was sterilized in the absence of γ-cyclodextrin.

EXAMPLE 4

[0206] The amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde formed, represented as the fraction (in %) of dexamethasone degraded to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes, in aqueous eye drops after no autoclaving (ie, heating to 121°C for 20 minutes) once, twice or three times is shown in Table 3.

TABLE 3

[0207] The amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde formed, represented as the fraction (in %) of dexamethasone degraded to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes, in aqueous eye drops without autoclaving (ie, heating to 121°C for 20 minutes), once, twice and three times is shown in continuation.

[0208] Formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde was observed at all four tested pHs. Although less 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde was formed at pH 7.0 than at 5.5, other degradation products appeared. According to the British Pharmacopoeia 2015 (Edition 19.0) the pH of an aqueous suspension of dexamethasone eye drops should be between 5.0 and 6.0.

EXAMPLE 5

[0209] The degradation of dexamethasone in F1 was investigated at 25°C, 40°C, 60°C, 70°C and 95°C. Apparent first-order rate constants for the disappearance of dexamethasone were determined, and the apparent activation energy was calculated using the Arrhenius equation. The equation is also used to estimate the first-order rate constant for the disappearance of dexamethasone at 25°C. The time for 10% (t90; shelf life) and 0.5% (t99.5) degradation was also calculated from the rate constants.

TABLE 4

[0210] In general, Eaopseg values of about 50 to 85 kJ/mol and values greater than 100 kJ/mol are very uncommon. The apparent Eaza dehydration of dexamethasone in aqueous γ-cyclodextrin to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes is 134.5 kJ/mol and, therefore, 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes are only formed in aqueous solutions of γ-cyclodextrin at extremely high temperatures.

EXAMPLE 6

[0211] The effect of the cooling rate on the size of the microparticles was investigated. The dexamethasone eye drop vehicle contains γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), benzalkonium chloride (0.02%), disodium edetate (0.10%), sodium chloride (0.57%) in purified water, all in w/v %. The vehicle is heated in an autoclave (121°C for 20 min) in a sealed vial to form a substantially clear solution. After cooling to 95°C, solid dexamethasone powder (1.50% w/v) was added to the solution. After the dexamethasone was dissolved (with stirring for 15 minutes), the solution was divided into small portions (approximately 5 ml) and placed in thermostatic water adjusted to different temperatures. Temperature changes were recorded against time. The particle size and viscosity of the resulting suspensions were determined.

EXAMPLE 7

[0212] The effect of sterilization time and temperature, and the effect of mixing time, are examined in the case of formulation F6. Formulations were prepared as described in Example 1. During formulation F6 the aqueous suspension of γ-cyclodextrin (Part B) and the separate aqueous suspension containing dexamethasone and all other ingredients except γ-cyclodextrin (Part A) were autoclaved at 121°C for 15 minutes. After autoclaving, the two suspensions/solutions were cooled to 95°C before mixing and then further cooled to ambient temperature (see Example 1 and Example 3).

[0213] Table 5 shows modified technological parameters during sterilization and mixing of γ-cyclodextrin in relation to other excipients and obtained amounts of the fraction broken down into 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes.

TABLE 5

[0214] Formulation F6a and F6b do not contain any γCD and show only the effect of the sterilization phase. F6a was sterilized in an autoclave once for 15 min at 121°C, while F6b was sterilized twice under the same conditions. One sterilization cycle added 0.05% 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde (% of total dexamethasone in eye drops), and two sterilization cycles added 0.10% 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde.

[0215] Formulation F6c shows a double mixing effect at 95°C after addition of γCD. An additional 15 minutes of mixing adds an additional 0.08% 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde in 0.20% F6.

[0216] Formulation F6d shows the effect of double autoclaving (two sterilization cycles) combined together with 15-minute stirring at 95°C after the addition of γCD. Double sterilization added an additional 0.05% of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde in 0.20% F6, matching the results of F6a and F6b formulations not containing γCD.

[0217] Formulation F6e shows the effect of styling at 135°C instead of 121°C for 15 min, followed by 15 min of stirring at 95°C after addition of γCD. The amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde increased from 0.20% to 0.34%.

[0218] The results show that the production process is robust and that small changes in the technological parameters will not substantially affect the amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehyde in the final product.

EXAMPLE 8

[0219] The production process F6 was applied at an industrial level. The composition of aqueous dexamethasone eye drops is as follows: dexamethasone (1.50% w/v), γ-cyclodextrin (14.00% w/v), poloxamer 407 (2.50% w/v), disodium edetate (0.10% w/v), sodium chloride (0.57% w/v) in purified water. The batch size was 400 liters (F15).

[0220] F15: Dexamethasone and all excipients except γ-cyclodextrin were dissolved or suspended in pure water at 80°C (solution A). γ-cyclodextrin was dissolved separately in pure water at 80°C (solution B). Solution A and solution B were sterilized at 121°C for 15 minutes. After sterilization and cooling, solution A and solution B were mixed. The mixture was then reheated to 95°C and kept at temperature with stirring for 15 minutes. The solution was cooled to 40°C in 40 minutes and then to room temperature (in an additional 40 minutes). The resulting microsuspension was then filled into unit dose containers. See Table 6.

TABLE 6

EXAMPLE 9

[0221] The composition of aqueous dexamethasone eye drops (F16) is as follows: dexamethasone (1.50%), γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), disodium edetate (0.10%), sodium chloride (0.57%) in purified water, all in w/v %. Excipients were separated into two parts, A and B. All A excipients, except γ-cyclodextrin, were dissolved in pure water at 80°C, and B γ-cyclodextrin was dissolved separately in pure water at 80°C. Dexamethasone is added to the excipient mixture immediately before sterilization. A mixture of excipients in water containing dexamethasone (A) and γ-cyclodextrin dissolved in water (B) was sterilized at 121°C for 15 minutes. After sterilization, A and B are mixed at 95°C. After stirring for 15 minutes, the solution was cooled from 95°C to 40°C at three different cooling rates (ΔT/Δt). The cooling rate of F16a is 17.7°C/min, that of F16b is 1.3°C/min and that of F16c is 1.2°C/min (table 7).

TABLE 7

Claims (15)

[0222] The table shows how the mean particle size is controlled by the cooling rate. The faster the cooling rate, the smaller the particles and the higher the viscosity. [0223] All numbers expressing amounts of ingredients, constituents, reaction conditions, and so forth used in the specification should be understood to be modified in all cases by the term "about." Without considering that the defined numerical ranges and parameters, the broad range of the subject matter presented herein are approximate values, the defined numerical value being indicated precisely as possible. Any numerical value, however, may inherently contain some error or inaccuracy as can be seen from the standard deviation from the respective measurement techniques. None of the features set forth herein should be construed as invoking 35 U.S.C. § 112(f), or pre-AIA ¶6, axis, if the term "means" is expressly used. Patent claims 1. Ophthalmological composition that includes, in an ophthalmologically acceptable base: solid complex comprising dexamethasone and γ-cyclodextrin, wherein that composition includes either (i) less than 1%, more particularly less than 0.8% by weight of any product not intentionally introduced into the composition according to this disclosure but generated in situ during the manufacture of that composition, relative to the weight of dexamethasone, or, (ii) less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2 wt.% dexamethasone enol aldehyde relative to the mass of dexamethasone. 2. Ophthalmic composition according to claim 1, wherein said composition further comprises a polymer, for example poloxamer. 3. Ophthalmic composition according to claim 2, in which the amount of polymer is 0.5 to 5%, more precisely 1 to 4%, even more precisely 2 to 3%, even more precisely 2.2 to 2.8 wt.% of polymer in relation to the volume of the composition. 4. Ophthalmic composition according to claim 3, wherein the viscosity of that composition is from 4 to 14 cP, preferably 5 to 13 cP, more preferably 6 to 12 cP. 5. Ophthalmic composition according to any one of claims 1 to 4, wherein dexamethasone is present in said composition at a concentration of 10 mg/mL to 20 mg/mL. 6. Ophthalmic composition according to any one of claims 1 to 5, in which 60 to 95 wt.%, more specifically 70 to 90 wt.%, of dexamethasone in that composition is in the form of a solid complex of dexamethasone and γ-cyclodextrin. 7. Ophthalmic composition according to any one of claims 1 to 6, in which the amount of γ-cyclodextrin is from 1 to 25%, more specifically 5 to 20%, even more specifically 10 to 18%, even more specifically 12 to 16 wt. % of γcyclodextrin in relation to the volume of the composition. 8. Ophthalmic composition according to any one of claims 1 to 7, wherein said composition includes: - 1 to 2% dexamethasone, for example 1.5% dexamethasone; - 12 to 16% γ-cyclodextrin, for example 14% γ-cyclodextrin; - 2.2 to 2.8% polymer, for example 2.5% poloxamer; - 0 to 0.2% stabilizer, for example 0.1% disodium medetate; - 0 to 1% electrolyte, for example 0.57% sodium chloride; and - water; where % represent wt.% in relation to the volume of the composition. 9. The procedure for preparing the ophthalmic composition, which includes the following stages: a) suspending the dexamethasone in an ophthalmically acceptable medium to form a suspension and heating said suspension until the dexamethasone is substantially dissolved in the ophthalmically acceptable medium; b) suspending the γ-cyclodextrin in an ophthalmically acceptable medium to form a suspension and heating said suspension until the γ-cyclodextrin is substantially dissolved in the ophthalmically acceptable medium; c) mixing the compositions from phases a) and b) at a temperature T1 lower than 120°C and heating the mixture at a temperature T1 lower than 120°C during time t; and d) cooling the resulting solution to temperature T2 in order to obtain an ophthalmic composition comprising a solid complex of dexamethasone and γ-cyclodextrin. 10. The method according to claim 9, wherein the temperature T180 to 110°C, more specifically 80 to 105°C, even more specifically 80 to 100°C. 11. The method according to claim 9 or 10, wherein the temperature T210 is up to 40°C, more specifically 15 to 35°C, even more specifically 20 to 30°C. 12. The method according to any one of claims 9 to 11, wherein the temperature T1 is cooled to the temperature T2 at a rate of 1 to 25°C/min, more specifically 2 to 20°C/min, even more specifically 5 to 18°C/min. 13. Ophthalmic composition obtainable by the process according to any one of claims 9 to 12, wherein said ophthalmic composition includes or (i) less than 1%, more particularly less than 0.8% by weight of any product not voluntarily introduced into the composition according to this disclosure but generated in situ during the manufacture of the composition relative to the weight of dexamethasone, or, (ii) less than 0.5%, more specifically less than 0.3%, even more specifically less than 0.2 wt.% dexamethasone enol aldehyde relative to the mass of dexamethasone. 14. An ophthalmic composition according to any one of claims 1 to 8 and 13, for use in the treatment of an eye condition, more specifically an anterior eye condition or a posterior eye condition, more specifically uveitis and macular edema. 15. Ophthalmic composition for use according to claim 14, wherein said composition is used in the form of eye drops.